Dr. Maragos is a dedicated physician/scientist who is strongly committed to a career as an academic neurologist. His scientific goal is to understand those factors that contribute to a nerve cell death. The candidate recently joined the Department of Neurology at the University of Kentucky as a tenure-track Assistant Professor. The Department of Neurology has provided him with a laboratory and the resources to purchase equipment and hire technical support. During the entire award period, he will spend 80% of his time on laboratory related activities. His sponsor, Don Gash, P.h.D. who is a leader in the field of basal ganglia research, will oversee his investigations. The strong Neuroscience community at the University will provide Dr. Maragos with essential intellectual interactions and potential for collaboration. In addition to research, the candidate will spend 15% of his time pursuing clinical activities, primarily in the area of movement and related neurodegenerative disorder. In the later years of the award, he will participate in molecular biology workshop at Cold Spring Harbor and work with scientists in the University to learn techniques he plans to incorporate into future studies. 5% of his time will be dedicated to teaching residents, graduate students and fulfilling limited administrative responsibilities. The primary goal of this proposal is to develop a novel in vivo method with which to creative reactive oxygen species (ROS) brain damage and to use this model to investigate the mechanism of ROS toxicity in rodent striatum. Dr. Maragos will inject inhibitors of antioxidant enzymes intracerebrally to induce tissue damage. He will assess the cytotoxic response using several histochemical methods with which he has experience and with immunohistochemical and neurochemical methodology (i.e., HPLC determination of ROS production) that he will learn during the award period. Using several approach to modify synaptic dopamine chemistry, he will use this model to investigate whether dopamine or its metabolite enhance ROS toxicity. He will study the reciprocal effects of ROS on NMDA receptor function by determining the effects on NMDA antagonists on ROS- induced tissue damage and whether ROS enhances NMDA receptor activation by measuring in vivo [3H] MK-801 binding to the open channel. It is expected that the proposed studies will provide valuable data about neurotransmitter involvement in ROS toxicity and allow development of mechanistically based therapeutics.